Thymus

 Thymus

PKGhatak, MD

In adults the Thymus gland exists only in name; from the newborn to childhood till the onset of puberty the thymus, sitting in front of the heart, dominates. The thymus in children is the largest gland in the chest. The Greeks thought it was the center of anger and named it thymus. The thymus name was derived from thumos meaning anger. Galen was the first physician who correctly described the evolution of the thymus in childhood and greatly reduced in size in adults. In adults, the thymus produces only a few mature   T-cells throughout life.

The thymus grows from the third and fourth pharyngeal pouches, one on each side. As the two lobes of the thymus grow, the cavities in the stalk are closed off and only a vestige remains. The developing thymus lobes descend in the thorax and move close together towards the center and finally join together as one thymus gland.

Several genes encode the development and maturation of the thymus. Deletion of chromosome 22 results in absence of the thymus and clinically the condition is known as DiGeorge syndrome. This syndrome is incompatible with life beyond a few weeks after birth.

Unlike the pancreas and liver, the thymus is just one gland - an endocrine gland. It secretes Thymosin and other hormones. The task of the thymus is to train the immature lymphocytes to become super sleuths like FBI agents. That task has two aspects - a Positive Selection - is the ability to detect any antigen that is foreign to the human body, and the other is a Negative Selection that quality is not to a mistake and call normal body antigens as foreign agents. The positive section is delineated by the presence of specific receptors on T cells surface that have the ability to recognize MHC immune antigen. MHC stands for major histocompatibility complex. Once the lymphocytes are trained properly, they are released into circulation with an official T-Cell designation. T- cells (thymic lymphocytes) take residence in lymph nodes, and spleen and move around the body in the blood. T-cells are further differentiated in CD (cluster differentiation) grouping based on the presence of cell surface proteins. Out of this classification, the CD4 and CD8 T- cells are well known since HIV/AIDs became prevalent. This acquired quality is called the Adaptive Immune System as opposed to Innate immunity, as for example- the macrophages engulf bacteria.

There is a complex relationship between Testosterone and gut bacterial antigen in the development of Positive and Negative Senses. Testosterone modifies gut bacterial antigen that elevates negative sense, whereas, Estrogen suppresses negative sense. XX chromosome in females and the master gene AIRE gene (Autoimmune regulator) regulate gene expression that codes autoimmunity are active participants in this process.

 Structure of Thymus.

Each thymus gland has an outer zone of densely packed cells called the cortex and a loose collection of cells in the inner zone called the medulla. Each lobe is made up of several lobules.

The cells of the cortex are mostly thymocytes - newly arrived lymphocytes from the bone marrow waiting to be turned into T-cells. The epithelial cells in the cortex are arranged as a fine network of cells supporting the thymocytes. In the cortex, the thymocytes acquire positive selection.

The medulla has a rough distribution of epithelial cells and fewer thymocytes and collections of whorls of epithelial cell remnants from the stock of the third pouch. These whorls are distinct microscopic features of the thymus and are known as Hassall's corpuscles. In the medulla, the thymocytes acquire negative selection.

 Hormones and Cytokines of Thymus:

Thymosin, Thymulin and Thymopoietin are three secretory hormones of the thymus. The first two are involved in T-cells transformation and the thymopoietin helps to keep the mature T-cells to keep up the acquired adaptive immune property. The cytokines are interleukin class IL1, IL 6, GM-CSF, zinc- thymulin complex and other polypeptides.

 Diseases associated with Thymus gland disorder:

Myasthenia gravis. In thymoma or hyperplasia of the thymus the T- cell functions are derailed. The body develops antibodies to Acetylcholine receptors. Lack of action of acetylcholine is felt as facial muscle weakness, weakness of legs and fatigue.

 DiGeorge syndrome: Deletion of chromosome 22 results in a congenital abnormality of the heart, hair lip and cleft palate, esophageal tracheal fistula, absence of Thymus gland and total failure of adaptive immunity of T-cells. If the condition is recognized early in infants Thymus gland transplant is indicated.

SCID: Severe combined immunodeficiency disease. This results from the deficient maturation of hemopoietic progenitor cells. T-cells, B-cells, NK (natural killer) cells are deficient.

Autoimmune endocrine syndrome: In this syndrome, T-cells fail to acquire the Negative Selection knowledge while developing in the medulla of the thymus. Thyroid, Parathyroid, and Adrenal cortex are destroyed due to autoantibodies and hormones from these endocrine glands become deficient. Candida infection of the mouth and GI tract is also a common feature of this entity.

Thymoma is associated with multiorgan autoimmunity. In this disorder, thymus growth disturbs the normal development of T-cells. The disease resembles Graft vs Host Disease.

The thymus gland is damaged by radiation of the chest and chemotherapy for cancer. Regeneration of the thymus is possible, shown recently in experimental animals. The CCL11 cells of the damaged thymus stroma initiate the recruitment of peripheral Eosinophils. The natural killer cells and Th2 cells inter-react with eosinophils and restoration of structure and functions resume.

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Liver

Liver

PKGhatak, MD

The liver is an amazing organ. It is the largest solid abdominal organ but hardly noticed. The liver is tucked away underneath the dome of the diaphragm and surrounded by a rib cage. Doctors want to examine the liver have to make it descend down with breathing (breathing out) by asking patients to breathe deep in and out and pushing his/her fingers deep underneath the right side of the rib cage. If the liver is palpable a normal liver is like the relaxed bicep muscle, a cirrhotic liver feels like ear cartilage.

The liver is the largest chemical factory of the body. It gets its raw materials from the GI tract, the digested food and drinks via the portal veins. Then the liver manufactures proteins, fat, cholesterol, glycogen from sugar and glucose from amino acids and fatty acids, hormones, enzymes, and other various chemicals; filters the waste products, detoxifies, absorbs toxins, and then releases these substances at the appropriate time in the blood. The liver is an endocrine cum exocrine gland and much more.

Embryology of Liver:

Liver growth starts early, as early as 2 weeks following fertilization of the ovum. An invagination of endoderm of the foregut, close to the Septum Trasvestum, occurs and that becomes the site of liver development. A liver bud develops and the cells of the head end of the liver bud start to grow in an empty space reserved for the heart and blood vessels. The developing cells destined to be liver cells grow like finger projections and orient in alternating rows with the endothelium of the blood vessels which later become the terminal capillary branches of the portal vein. The septum trasvestum becomes the capsule of the liver and fibrous tissues from the capsule enter the developing liver cells and become the scaffolding and provide stability of the liver. The tail end of the same liver bud forms the gall bladder and extrahepatic bile ducts.

Liver lobule:

The liver is a mixture of the exocrine gland, endocrine gland, vascular organ and storehouse of many things including every Stem Cell line.

The structural and functional unit of the liver is a lobule – a tiny acinus. The total number of lobules in a liver is estimated to be 300 billion. An understanding of microscopic anatomy is essential to study the physiology of the liver.

A liver lobule is a three dimensional unit. It looks hexagonal under the microscope but in a living state, a lobule is more or less like a circular structure. At the periphery, there is an arcade formed by a branch of the portal vein. Straight branches, the venules of the portal vein – often referred as a lake, originate from the arcade and travel toward the center of the lobule and converse on a central vein. The appearance resembles the spokes of a wheel. Columns of liver cells follow closely the straight portal venules. The other side of the liver cells column is a draining tube – a tiny bile duct. This pattern is repeated in all lobules. The interlobar space is interlaced with fine fibrous tissues attached to the liver capsule. This space contains branches of the hepatic artery and lymph vessels and various mesenchymal cells, including the well known Kupffer's cells.

Branches of the hepatic artery, bile duct and lymphatics follow the branches of the portal vein. a hepatic artery branch to the lobule opens into the lake. The plexus of fine branches of the hepatic artery supplies all the cells of the bile duct and other structures in a lobule. The central vein joins with adjoining veins and ultimately forms 2 to 4 Hepatic veins and hepatic veins terminate in the Superior Vena Cava.

In essence, each hepatic cell is bathed by the blood that is a mixture of arterial blood and venous blood returning from the GI tract. Intrahepatic bile ducts are as profuse as blood vessels are and lobules are drained continuously.

A Hepatocyte:

A liver cell is a large cell and rich in the cytoplasm and nuclear materials. The nucleus is surrounded by a well demarcated nuclear wall. The nuclear chromatin is very prominent and generally contains two nucleoli. The cytoplasm is loaded with mitochondria, smooth and rough endoplasmic reticulum, Golgi apparatus, lysosome, peroxisome, inclusion bodies, stored glycogen, and lipid molecules.

Blood supply: The liver is a very vascular organ. It weighs just 2 % of the body weight but gets 25 % of cardiac output. Of the total blood inside the liver, 75 % is from the portal vein, and the rest is arterial. The liver stores 15 % of total body blood and in hemorrhage, hepatic blood is made available.

Bile secretion: In a day about 1 liter of bile is produced. Bile is produced continuously and finds its way to the gall bladder first and is stored there. After a fatty meal gall bladder discharges bile into the intestine.

Liver Function: It is said that the liver completes 500 different tasks.

The following are just to name some of these functions.

Metabolism of Carbohydrate: Every aspect of carbohydrate metabolic processes from energy production, breakdown of glycogen, making glucose from fat and amino acids and conjugation of the carbohydrate moiety to toxic substances take place in the liver.

Fat metabolism: Cholesterol is synthesized in the liver. The liver converts fatty acid to fat molecules and breaks down fat and releases fatty acid in starved conditions.

Protein synthesis: Albumin and ferritin are made in the liver, so also all the transport proteins - just too many to mention here.

Acute phase positive proteins are about 30 in number. Some important are C- reactive protein, procalcitonin, alpha antitrypsin, heptidine,  IL-1 receptor antagonist, D- dimer. The negative acute phase proteins are albumin, transferrin, transthyretin. 

Blood coagulation: Several anticoagulants and clotting factors are made in the liver. Anticoagulants are protein S and protein C, Antithrombin. Coagulants are fibrinogen, prothrombin, factors- V, VII, IX, X, XI, XII. Von Willebrand and factor VIII are made in the liver but not by the hepatocytes.

Hormone production: Thrombopoietin, Somatomedin, Angiotensinogen, Hepcidin.

Vitamins production: Vitamin D 25-OH. The liver acts as a store of fat-soluble vitamins- A, D, E, K. and B12.

Storage function: Iron, Glycogen, fat, copper.

Detoxification: Most toxins are made less toxic or harmless by conjugation wand made sulfate, glucuronide and simply converted to inert substances.

Execratory function: Bile acids and bilirubin.

Digestive function: Bile acids and bicarbonates.

Myeloid Metaplasia and liver: Several hematological conditions end up destroying bone marrow and replaced it with fibrous tissue, a condition known as myelofibrosis. In such conditions liver and spleen attempt to generate deficient blood cells.

Regenerative power: The liver carries all stem lines. At little as 15 % of the liver remaining from an accident or liver donation, the remaining liver will regenerate to the normal size.

Liver transplant began in 1967, it has become an essential operation in congenital biliary atresia. A liver transplant is performed for liver failure due to many causes including alcoholic cirrhosis and viral hepatitis C.

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Pancreas

Pancreas

PKGhatak, MD

The pancreas is an important organ but not essential to life since the isolation and purification of Insulin in 1921 by Dr. Banting and a medical student Mr. Best. The pancreas is a mixed gland contains both exocrine (secretion by duct) and endocrine (secretion directly enters blood) glands.

Development of Pancreas:

The pancreas has two sources of origin. Two independent buds develop from the foregut endoderm - one dorsal bud and one ventral bud, at the junction of the foregut and midgut, next to the origin of the biliary bud. The dorsal bud produces the major part of the gland and the main duct, the ventral bud produces a part of the head, uncinate process and the accessory duct.

Exocrine development:

In the beginning, the primitive pancreatic cells differentiate into the acinar cell line (gland with ducts) and endocrine cell line. Each acinar duct joins with the adjoining acini and ultimately forms two major ducts as mentioned above. Each acinar duct joins with the adjoining acini and ultimately forms two major ducts as mentioned above. The main pancreatic duct opens into the 2nd part of the duodenum and the duct is a bit dilated called the ampulla of Vater and is surrounded by smooth muscle sphincter- sphincter of Oddi. The common bile duct joins the pancreatic duct in the ampulla and the opening in the pancreatic duct is guarded by the sphincter of Boyden. The accessory pancreatic duct opens just proximal to the bile duct+ pancreatic duct opening. In adults, many congenital anatomical variations of pancreatic ducts and the occasional head of the pancreas are encountered during surgery.

Endocrine Development:

The developing endocrine cells are grouped together in several clusters and are widely dispersed all through the gland. These clusters are called Langerhans Islands. Endocrine cell populations are further divided into alpha, beta, delta and C cells. All these cells are present on every island. Initial tiny ducts are attached to each islet but soon the ducts disappear.

Location of Pancreas:

The pancreas is located deep inside the abdomen on the posterior abdominal wall, behind the peritoneum. It is firmly anchored on the wall; the head of the pancreas fills the c-shaped space of the duodenal curvature, the main body lies across the abdominal wall, the tail part almost touching the spleen. In front of the pancreas is the Lesser Sac of the Omentum, the stomach slides over it easily.

Exocrine Function of Pancreas:

Pancreatic enzymes are secreted by acini cells and are rich in digestive enzymes -

Pancreatic Amylase, Trypsin, Chymotrypsin, Lipase, Phospholipase, Cholesterol esterase. In addition, the ductal cells secrete Chloride and Bicarbonate.

The total volume of pancreatic secretion is 2 to 3 liters. a day.

The pancreatic juice is very alkaline and acts with bile neutralizes highly acidic gastric discharge in the duodenum.

The action of Pancreatic enzymes on Food:

As the names imply, the amylase digests complex carbohydrates into glucose, trypsin and chymotrypsin digest proteins into simple amino acids and Lipase digest fat into fatty acid and glycerol, cholesterol ester breaks down cholesterol. In the digestive process, duodenal enzymes play a significant part also.

Endocrine Function of Pancreas:

Alpha cells secrete Glucagon.

Beta cells secrete Insulin and Amylin.

Delta cells secrete Somatotropin, Ghrelin and Pancreatic polypeptides. Gastrin is secreted in an early stage of development and later the stomach secretes gastrin exclusively.

 The C-cell function is not known.

The action of Glucagon. Glucagon breaks down glycogen stores in the liver and skeletal muscles. It stimulates amino acid conversion to glucose (neogluconogenesis). Glycogen turns fatty acids into fat molecules in the liver. Glucagon delays the release of Insulin from the pancreas.

The action of Insulin.  Insulin binds with insulin receptors present on the surface of every cell. A protein molecule GLUT4(glucose transporter 4) comes up to the surface of the cells and an Insulin molecule bound to the receptor fuses with the membrane. This opens up channels for glucose molecules to enter the inside of the cell. The glucose molecule is immediately converted to glucose phosphate by the enzyme phosphatase. This keeps the concentration gradient in favor of glucose crossing inside the cells. Insulin favors glycogen synthesis, the conversion of fatty acids to fat molecules and amino acids to protein. Insulin promotes body growth and increases growth hormone secretion from the pituitary gland. Insulin delays glucagon secretion and thereby reduces glycogen breakdown.

The action of Somatostatin. Somatostatin is a gastrointestinal motility inhibitor. Somatostatin decreases both exocrine and endocrine secretion of the pancreas, decreases secretions from the duodenal and small intestinal glands. It reduces growth hormone release from the pituitary gland. It reduces gastric motility, gastric acid and gastrin secretion.

The action of pancreatic polypeptides. These small molecules suppress pancreatic exocrine secretion, gall bladder contraction and gastric motility.

The action of Ghrelin. Ghrelin promotes growth hormone release, muscle growth, increases appetite. 

Blood Supply of Pancreas: Pancreas is richly supplied by arterial circulation. Celiac artery and Superior mesenteric artery supply arterial blood. The venous drainage goes to the liver by the Portal vein.

Insulin sensor: The alpha and beta cells act as the sensor of blood glucose levels. Alfa cells modify glucagon release by a negative feedback loop; whereas the beta cells release more insulin when sugar levels are high and shunt down Insulin release when the sugar level is low.

Nerve Supply of Pancreas. Like every abdominal organ, the pancreas has two nervous systems innervation - namely Somatic and Autonomic nervous systems. Nerve fibers going in and out of the pancreas pass through the celiac ganglion but many fibers just pass through.

Somatic sensory. The nerve cells are located in the Dorsal Root Ganglia (DRG) of the spinal nerves T 6 to L 2. The nerve fibers carrying the pain and other sensations enter the spinal cord and travel along the intermediate lateral tract of the spinal cord to the nuclei of the Thalamus. The 2nd order neurons from the thalamus cross the midline to reach the cerebral cortex. The DRG is sensitive to Capsaicin, CGRP (calcitonin gene related peptide). The neurons generate substance P.

Motor division.  The main center for secretary and contractile functions are located in the Nodosa Ganglion of the Vegas nerve. The axions from these neurons directly innervate all the cells of the pancreas.

Autonomic Nervous System:

Sympathetic supply. The nerve cells are located in the Celiac ganglion, Mesenteric ganglia, Paravertebral ganglia. The alpha fibers of sympathetic nerves produce vasoconstriction, delays secretion and decreases endocrine function. Beta fibers stimulate Insulin and glucagon production and release.

Parasympathetic Nervous System:

The nerve cells are located in the Dorsal ganglia of the Vegas nerve. The axion of these nerves makes connections with the neuron present in the pancreas itself. Parasympathetic stimulation increases both exocrine and endocrine secretion and production.

Neurotransmitters:

Somatic nerves are Cholinergic. Sympathetic nerves are noradrenergic, glycinergic, and respond by releasing Neuropeptide gamma. Parasympathetic nerves are nicotinic-cholinergic at the ganglia and muscarine choline at the postganglionic terminal fibers.

The pancreas is fully developed at birth but only the exocrine function is present at birth. At about 15 weeks of life, the endocrine function begins.

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